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Background: Bivalent regions of chromatin (BvCR) are characterized by trimethylated lysine 4 (H3K4me3) and lysine 27 on histone H3 (H3K27me3) deposition which aid gene expression control during cell differentiation. The role of BvCR in post-transcriptional DNA damage response remains unidentified. Oncoprotein survivin binds chromatin and mediates IFNγ effects in CD4+ cells. In this study, we explored the role of BvCR in DNA damage response of autoimmune CD4+ cells in rheumatoid arthritis (RA). Methods: We performed deep sequencing of the chromatin bound to survivin, H3K4me3, H3K27me3, and H3K27ac, in human CD4+ cells and identified BvCR, which possessed all three histone H3 modifications. Protein partners of survivin on chromatin were predicted by integration of motif enrichment analysis, computational machine-learning, and structural modeling, and validated experimentally by mass spectrometry and peptide binding array. Survivin-dependent change in BvCR and transcription of genes controlled by the BvCR was studied in CD4+ cells treated with survivin inhibitor, which revealed survivin-dependent biological processes. Finally, the survivin-dependent processes were mapped to the transcriptome of CD4+ cells in blood and in synovial tissue of RA patients and the effect of modern immunomodulating drugs on these processes was explored. Results: We identified that BvCR dominated by H3K4me3 (H3K4me3-BvCR) accommodated survivin within cis-regulatory elements of the genes controlling DNA damage. Inhibition of survivin or JAK-STAT signaling enhanced H3K4me3-BvCR dominance, which improved DNA damage recognition and arrested cell cycle progression in cultured CD4+ cells. Specifically, BvCR accommodating survivin aided sequence-specific anchoring of the BRG1/SWI chromatin-remodeling complex coordinating DNA damage response. Mapping survivin interactome to BRG1/SWI complex demonstrated interaction of survivin with the subunits anchoring the complex to chromatin. Co-expression of BRG1, survivin and IFNγ in CD4+ cells rendered complete deregulation of DNA damage response in RA. Such cells possessed strong ability of homing to RA joints. Immunomodulating drugs inhibited the anchoring subunits of BRG1/SWI complex, which affected arthritogenic profile of CD4+ cells. Conclusions: BvCR execute DNA damage control to maintain genome fidelity in IFN-activated CD4+ cells. Survivin anchors the BRG1/SWI complex to BvCR to repress DNA damage response. These results offer a platform for therapeutic interventions targeting survivin and BRG1/SWI complex in autoimmunity. [ABSTRACT FROM AUTHOR]

Background: The amount of time spent living with disease greatly influences elderly people's wellbeing, disability and healthcare costs, but differs by disease, age and sex.Methods: We assessed how various single and combined diseases differentially affect life years spent living with disease in Dutch elderly men and women (65+) over their remaining life course. Multistate life table calculations were applied to age and sex-specific disease prevalence, incidence and death rates for the Netherlands in 2007. We distinguished congestive heart failure, coronary heart disease (CHD), breast and prostate cancer, colon cancer, lung cancer, diabetes, COPD, stroke, dementia and osteoarthritis.Results: Across ages 65, 70, 75, 80 and 85, CHD caused the most time spent living with disease for Dutch men (from 7.6 years at age 65 to 3.7 years at age 85) and osteoarthritis for Dutch women (from 11.7 years at age 65 to 4.8 years at age 85). Of the various co-occurrences of disease, the combination of diabetes and osteoarthritis led to the most time spent living with disease, for both men (from 11.2 years at age 65 to 4.9 -years at age 85) and women (from 14.2 years at age 65 to 6.0 years at age 85).Conclusions: Specific single and multi-morbid diseases affect men and women differently at different phases in the life course in terms of the time spent living with disease, and consequently, their potential disability. Timely sex and age-specific interventions targeting prevention of the single and combined diseases identified could reduce healthcare costs and increase wellbeing in elderly people. [ABSTRACT FROM AUTHOR]

Background: Assessing quality of life among the elderly is a complex and multifaceted issue. Elderly people might find valuing and describing their personal experience of quality of life (QoL) demanding and cumbersome. This study therefore sought to determine the feasibility of administering two questionnaires in two samples of elderly people.Methods: A preference-based instrument (EQ-5D + C) and a currently achieved functioning questionnaire (CAF) were utilized. Two pilot studies were performed. The first was performed in South Africa (n = 30), designed to test whether elderly respondents could complete and understand the two questionnaires and also to indicate which valuation method, visual analogue scale or time trade off they preferred. A second pilot study was performed in the Netherlands (n = 30), designed to investigate the use of both questionnaires in determining quality of life and health state valuations in a Dutch sample of elderly.Results: Seventy percent of the South African respondents indicated that they preferred the visual analogue scale (VAS) method, when compared to the time trade-off (TTO). In both the South African and the Dutch pilot studies, the respondents, with different dependency levels, were able to use both questionnaires to determine health state descriptions and valuations. When ranking the profiles from fewer to more problems, the EQ-5D + C exhibits a gradual downwards trend, with a maximum of 100 and minimum VAS value of 41. The CAF also exhibits a gradual downwards trend, with a maximum of 1.00 and minimum VAS value of 36.Conclusions: The results indicate that individuals from different parts of the world are able to complete, describe, and value the questionnaires. It is our recommendation that a comprehensive study should be done, which includes both the EQ-5D + C questionnaire and the CAF questionnaire, since the two questionnaires have proven to be feasible in providing information on quality of life and well-being of elderly people. [ABSTRACT FROM AUTHOR]

Background: Sunitinib has become mainstay first line treatment for patients with metastatic renal clear cell carcinoma (mRCC). Still, useful predictive markers of response are lacking and urgently needed for clinical decision making.Methods: In the present study we investigated the predictive value of standard serum markers as well as clinical markers, including C-reactive protein (CRP), Neutrophil to Lymphocyte ratio (NLR) and early hypertension (eHTN) in an unselected prospective patient population treated with sunitinib for mRCC. Forty-six patients were enrolled in a prospective single-arm study of predictive markers for sunitinib response. Response rates according to RECIST 1.1 were used as primary end-point. Secondary objectives were to evaluate prognostic value of the candidate markers with regard to progression free survival (PFS) and overall survival (OS). In addition, toxicity rates and quality of life was recorded.Results: Median PFS and OS was 9.1 months and 15.0 months, respectively. Of 38 patients evaluable for response, 1 patient had complete response (CR), 7 had partial response (PR), 18 had stable disease (SD) and 12 had progressive disease (PD). Normal CRP at baseline was significantly associated with objective response (CR + PR) (p = 0.01). Normal CRP was also significantly associated with improved PFS and OS (Log rank, p = 0.05 and <0.01, respectively). Early hypertension, NLR and IMDC risk score were not significantly associated with response rates or survival.Conclusion: Baseline CRP was a significant predictive factor of sunitinib response and a prognostic factor of survival. Baseline CRP might be a useful biomarker in the treatment planning of mRCC. Due to the relatively small sample size, our results need to be confirmed in larger studies. [ABSTRACT FROM AUTHOR]

Background: Birth centres are described as settings where women with uncomplicated pregnancies can give birth in a home-like environment assisted by midwives and maternity care assistants. If complications arise or threaten, the woman is referred to a maternity unit of a hospital where an obstetrician will take over responsibility. In the last decade, a number of new birth centres have been established in the Netherlands, based on the assumption that birth centres provide better quality of care since they offer a better opportunity for more integrated care than the existing system with independent primary and secondary care providers. At present, there is no evidence for this assumption. The Dutch Birth Centre Study is designed to present evidence-based recommendations for organization and functioning of future birth centres in the Netherlands. A necessary first step in this evaluation is the development of indicators for measuring the quality of the care delivered in birth centres in the Netherlands. The aim of this study is to identify a comprehensive set of structure and process indicators to assess quality of birth centre care.Methods: We used mixed methods to develop a set of structure and process quality indicators for evaluating birth centre care. Beginning with a literature review, we developed an exhaustive list of determinants. We then used a Delphi study to narrow this list, calling on experts to rate the determinants for relevance and feasibility. A multidisciplinary expert panel of 63 experts, directly or indirectly involved with birth centre care, was invited to participate.Results: A panel of 42 experts completed two Delphi rounds rating determinants of the quality of birth centre care based on their relevance (to the setting) and feasibility (of use). A set of 30 determinants for structure and process quality indicators was identified to assess the quality of birth centre care in the Netherlands.Conclusions: We identified 30 determinants for structure and process quality indicators concerning birth centre care. This set will be validated during the evaluation of birth centres in the Dutch Birth Centre Study. [ABSTRACT FROM AUTHOR]

Background: Atherogenic dyslipidemia is associated with poor cardiovascular outcomes, yet markers of this condition are often ignored in clinical practice. Here, we address a clear evidence gap by assessing the prevalence and treatment of two markers of atherogenic dyslipidemia: elevated triglyceride levels and low levels of high-density lipoprotein cholesterol.Methods: This cross-sectional observational study assessed the prevalence of two atherogenic dyslipidemia markers, high triglyceride levels and low high-density lipoprotein cholesterol levels, in the study population from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA; N = 7641; of whom 51.6% were female and 95.6% were White/Caucasian). The EURIKA population included European patients, aged at least 50 years with at least one cardiovascular risk factor but no history of cardiovascular disease.Results: Over 20% of patients from the EURIKA population have either triglyceride or high-density lipoprotein cholesterol levels characteristic of atherogenic dyslipidemia. Furthermore, the proportions of patients with one of these markers were higher in subpopulations with type 2 diabetes mellitus or those already calculated to be at high risk of cardiovascular disease. Approximately 55% of the EURIKA population who have markers of atherogenic dyslipidemia are not receiving lipid-lowering therapy.Conclusions: A considerable proportion of patients with at least one major cardiovascular risk factor in the primary cardiovascular disease prevention setting have markers of atherogenic dyslipidemia. The majority of these patients are not receiving optimal treatment, as specified in international guidelines, and thus their risk of developing cardiovascular disease is possibly underestimated.Trial Registration: The present study is registered with ClinicalTrials.gov (ID: NCT00882336). [ABSTRACT FROM AUTHOR]

Background: In child and youth care, quantitative estimates of the impact of serious behaviour problems have not yet been made. Such input is needed to support decision making on investments in treatment. The aim of this paper was to elicit valuations of social and conduct disorders in children and adolescents from three different perspectives: professionals, youth, and parents. Methods: We obtained valuations from 25 youth care professionals, 50 children (age 9-10) without serious behaviour problems and 36 adolescents (age 16-17) with and without serious behaviour disorders, and 46 parents with children in the aforementioned age categories. Valuations were estimated from 18 descriptions of behaviour disorders in youth aged 9 and 15 years. Descriptions included Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), and Disruptive Behaviour Disorder (DBD). Comorbid conditions were Attention Deficit Hyperactivity Disorder and substance abuse. Valuations were obtained with the EuroQol questionnaire (EQ-5D-3 L) and a visual analogue scale (VAS). Results: Valuations were generally severe; problems were by and large reported to worsen quality of life by 50% compared to being fully healthy. Professionals regarded DBD with substance abuse as most severe (VAS values 0.41 for children, and 0.43 for adolescents, i.e. less than half of normal). They rated ODD as least severe (VAS values 0.58 for children, 0.59 for adolescents). Children, adolescents and parents gave lower valuations than professionals, and had a wider range of scores, particularly at the lower end of the scale. Conclusions: Behaviour disorders pose a formidable burden from the perspectives of professionals as well as children, adolescents and parents. These results may support medical decision making to set priorities with regard to prevention and treatment based on perceived severity. [ABSTRACT FROM AUTHOR]